RESEARCH PROJECTS

1) Genetic functional analysis of the neoblasts, the pluripotent planarian stem cells

Neoblasts are the only mitotically active cells in planarians and, as such, are responsible for replacing tissues during homeostatic turnover as well as after any injury. Analysis of the mechanisms controlling the maintenance of an undifferentiated state of stem cells is of critical importance for the understanding of various biological phenomena, such as embryonic development, regeneration, and neoplastic transformation. It is also, therefore, one of the keys for the development of therapeutic applications in the field of regenerative medicine, induced pluripotent stem cells (iPSC) and cancer. However, the molecular mechanisms underlying the crosstalk between stem cells and their surrounding differentiated tissues are largely unknown.

Using FACS and cell sorting together with digital gene expression (DGE) strategy, we identified weakly expressed genes, from the differentiating neoblasts sub-population that will define new cell lineages. Their role is currently being studied by RNAi interference.

 

Principal Investigator
Dr. Emili Saló

Predocs
Alejandro Gonzalez-Sastre
Jose Ignacio Rojo

2) Intercellular communication and patterning: Role of the Wnt pathway

The great morphologic plasticity of flatworms is shown by their ability to regenerate a perfectly patterned organism from any small fragment of their body . This capacity is not only due to the presence of pluripotent stem cells, the neoblasts, but also to the constitutive activation of the main intercellular communication signalling pathways, like happens during embryonic development. This is one of the conclusions from our studies about the role of the BMP and Wnt pathways in adult planarians.I The striking phenotypes generated after inhibition of several elements of both pathways clearly demonstrate that those developmental signals are evolutionary conserved in the establishment of the D/V and A/P axis, respectively, and that they are re-used in a post-embryonic context. Moreover,, those studies are converting planarians to an essential model to clarify the mechanisms which control maintenance/proliferation of stem cells (neoblasts), their differentiation to the proper lineage and the acquisition of the final fate.

Currently, we focus our research on the role of the Wnt signalling in two planarian species, Schmidthea mediterranea and Schmidthea polychroa. The functional analysis of Wnt activators and Wnt inhibitors supports and scenario in which the nested activation of posterior wnts, together with the inhibitory function of anterior repressors, generates a posterior to anterior gradient of activity of β-catenin-1, responsible for the specification of the A/P body axis of adult planarians. Thus, silencing of β-catenin-1 or posterior Wnts leads to an anteriorization of planarians, which extreme phenotype are radial-like fully anteriorized animals. On the contrary, silencing of β-catenin-1 repressors leads to posteriorized animals.. In order to corraborate this model, we are analyzing the dynamics of activation of β-catenin-1, as well as the functionality of Wnt receptors, the Frizzleds family, composed by 11 members which are mostly expressed between the neoblast population.

During the last years we include in our studies the sexual species S. polycrhoa with the aim to study the Wnt function during embryogenesis and during sexual maturation. This approach offers theunique opportunity to directly compare the processes of embryogenesis, regeneration and homeostasis in the same model.

We have also boarded the study of the non canonical or β catenin-indepenedent Wnt pathway. Planarians Wnt5 conserve a non-canonical role in planarians, being required for the medio-lateral positioning of the central nervous system. Currently we are studying its putative receptors (Frizzleds, Ror, RYK/Derailed) in order to clarify the molecular nature of this function. Finally, we have reported the functionality of the non-canonicak Wnt/PCP network in planarians, showing that dishevelled, together with Van Gogh and diversin, is essential for the correct apical positioning of the cilia in the planarian epidermis. This is the first report about the functionality of the PCP signalling in any Lophotrocozoan.

Principal Investigator
Dra. Teresa Adell

Predocs
Miquel Sureda

3) The early response to injury: wound healing, proliferation, apoptosis and size control

The stimulus for regeneration is injury. A strong muscle contraction at the site of wounding occurs within seconds and minimizes the surface area of the wound. But regeneration is a complex biological process that requires the production of new tissue by neoblastsproliferation and remodelation of the old fragments, to produce a complete and proportionated new flatworm, by apoptosis. We have characterized the role of the JNK pathway, a stress-activated protein kinase cascade, in response to planarian injury in the control of the mitotic and apoptotic response during planarians regeneration, as well as during homeostatic growth and degrowth.

Another important player to get a proper and functional regenerated organisms is the Hippo-Yorkie pathway, which is responsible for controlling cell proliferation and organ size in other models. We are analyzing weather planarian Hippo pathway plays a role in the control of size and growth in planarians, and its possible relationship with the JNK pathway for the achievement of the correct proportions.

Principal Investigators
Dr. Emili Saló
Dra. Teresa Adell

Predocs
Nidia DeSouza
SELECTED PUBLICATIONS

Articles

Sureda-Gómez M, Pascual-Carreras E, Adell TPosterior Wnts Have Distinct Roles in Specification and Patterning of the Planarian Posterior Region. Int J Mol Sci. 2015 Nov 5;16(11):26543-54. doi: 10.3390/ijms161125970.

Almuedo-Castillo M, Crespo-Yanez X, Seebeck F, Bartscherer K, Salò E, Adell T. JNK controls the onset of mitosis in planarian stem cells and triggers apoptotic cell death required for regeneration and remodeling. PLoS Genet. 2014 Jun 12;10(6):e1004400. doi: 10.1371/journal.pgen.1004400. eCollection 2014 Jun. Erratum in: PLoS Genet. 2015 Apr;11(4):e1005132.

M.E. Isolani; J.F. Abril; E. Saló; P. Deri; A.M. Bianucci; R. Batistoni Planarians as a Model to Assess In Vivo the Role of Matrix Metalloproteinase Genes during Homeostasis and Regeneration. PLOS ONE, 2013, 8(2):e55649

Emili Saló and Kiyokazu Agata. Planarian regeneration: a classic topic claiming new attention. Int. J. Dev. Biol. 56: 1-4, 2012

Alejandro Gonzalez-Sastre, Mª Dolores Molina and Emili Saló. Inhibitory Smads and Bone Morphogenetic Protein (BMP) modulate anterior photoreceptor cell number during planarian eye regeneration. Int. J. Dev. Biol. 56: 155-163, 2012

Almuedo-Castillo M, Sureda-Gómez M, Adell TWnt signaling in planarians: new answers to old questions. Int J Dev Biol. 2012;56(1-3):53-65. doi: 10.1387/ijdb.113451ma. Review.

Auletta, G., Adell, T., Colagè, I., D’Ambrosio, P.; Salò, E. Space Research Program on Planarian Schmidtea mediterranea’s Establishment of the Anterior-Posterior Axis in Altered Gravity Conditions. Microgravity 2012. ISSN 0938-0108.

Josep F. Abril, Francesc Cebrià, Gustavo Rodríguez-Esteban, Susanna Fraguas, Thomas Horn, Beatriz Calvo, Kerstin Bartscherer, and Emili Saló. Smed454 dataset: unravelling the transcriptome of Schmidtea mediterranea. BMC genomics [Highly Accessed mention], 11(731):e1-e19, 2010

Mª Dolores Molina, Ana Neto, Ignacio Maeso, José Luis Gómez-Skarmeta, Emili Saló and Francesc Cebrià. Noggins, a noggin-like gene and a BMP/ADMP organizer control the regeneration of the planarian DV axis. Current Biology 21:300-305, 2011

Maria Almuedo-Castillo, Emili Saló and Teresa Adell. Dishevelled is essential for neural connectivity and Planar Cell Polarity in planarians. Proc. Natl. Acad. Sci. 2011, 108; 2813-2818

Enrique Fernández-Taboada, Gustavo Rodríguez-Esteban, Emili Saló, Josep F Abril. A proteomics approach to unravel the molecular nature of planarian stem cells. BMC genomics [Highly Accessed mention], 12(133):e1-e13, 2011

Marta Iglesias, Maria Almuedo-Castillo, Aziz Aboobaker and Emili Saló. Early planarian brain formation is independent of regenerative polarity mediated by the Wnt/bcatenin pathway. Developmental Biology 358: 68-78, 2011

Mª Dolores Molina, Emili Saló and Francesc Cebrià. Organizing the DV axis during planarian regeneration. Communicative & Integrative Biology 4:4, 498-500, 2011

Guoliang Chai, Changxin Ma, Kai Bao, Liang Zheng, Xinguan Wang, Zhirong Sun, Emili Saló, Teresa Adell, Wei Wu. Complete functional segregation of planarian b-catenin1 and -2 in mediating Wnt signaling and cell adhesion. J Biol Chem 31: 24120-24130, 2010

Enrique Fernandéz-Taboada, Sören Moritz, Martin Stehling, Dagmar Zeuschner , Hans R. Schöler, Emili Saló and Luca Gentile. Smed-SmB, a member of the (L)Sm protein superfamily, is essential for chromatoid body organization and planarian stem cell proliferation. Development 137: 1055-1065, 2010

Cristina González-Estévez and Emili Saló. Autophagy and apoptosis in planarians. Apoptosis 15: 279-292, 2010

Adell, T., Saló, E., Boutros, M., and Bartscherer, K. Smed-Evi/Wntless is required for b-catenin dependent and -independent processes during planarian regeneration. Development 136: 905-910; 2009

Emili Saló, Josep F. Abril, Teresa Adell, Francesc Cebrià, Kay Eckelt, Enrique Fernández-Taboada, Mette Handberg-Thorsager, Marta Iglesias, María D. Molina and Gustavo Rodríguez-Esteban. Planarian regeneration: achievements and future directions after 20 years of research. International Journal of Developmental Biology, 53: 1317-1327; 2009

Maria Dolores Molina; Francesc Cebria; Emili Saló. Expression pattern of the expanded noggin gene family in the planarian Schmidtea mediterranea. Mech. Dev. Gene expression Pattern, en premsa, 2009

Mette Handberg-Thorsager, Enrique Fernandez and Emili Saló. Stem cells and regeneration in planarians. Frontiers in Bioscience 13:6374-6394; 2008

Marta Iglesias; Jose Luis Gomez-Skarmeta; Emili Saló; Teresa Adell. Silencing of Smed-β-catenin1 generates radial-like hypercephalized planarians. Development 135; 1215-1221; 2008

Teresa Adell, Maria Marsal and Emili Saló. Planarian GSK3s are involved in neural regeneration. Dev. Genes. & Evol. 218, 89-103; 2008

Gianluca Tettamanti1, Emili Saló, Cristina González-Estévez, Daniel A. Felix, Annalisa Grimaldi and Magda de Eguileor. Autophagy in Invertebrates: Insights Into Development, Regeneration and Body. Remodeling. Current Pharmaceutical Design 14, 116-125; 2008

Cristina González-Estévez, Daniel A. Felix, Aziz A. Aboobaker and Emili Saló. Gtdap-1 and the Role of Autophagy During Planarian Regeneration and Starvation. Autophagy 3; 6 ; 640-642; 2007

Maria Dolores Molina; Francesc Cebria; Emili Saló. The BMP pathway is essential for re-specification and maintenance of the dorsoventral axis in regenerating and intact planarians. Developmental Biology 311; 79-94; 2007

Cristina González-Estévez, Daniel A. Felix, Aziz A. Aboobaker and Emili Saló. Gtdap-1 promotes autophagy and is required for planarian remodelling during regeneration and starvation. Proc. Natl. Acad. Sci. 104; (33); 13373-13378; 2007

CONTACT _Con-4062F8461 \c \s \l Mette Handberg-Thorsager and Emili Saló. The planarian nanos-like gene Smednos is expressed in germline and eye precursor cells during development and regeneration. Dev. Genes. & Evol. 217(5);403-411; 2007

Araúz, P.A., E. Saló, F. Mestres, and L. Serra. New wing and eye mutations in D. subobscura. Mutation notes. DIS 89, 138- 139, 2006

Jiménez, E., Paps, J., García-Fernàndez J. & Saló, E. Hox and paraHox genes in nemertodermatida, a basal bilaterian clade. Int. J. Dev. Biol. 50; 675-679; 2006

Saló, E. The power of regeneration and the stem cells kingdom: The freshwater planarianSchmidtea mediterranea (Platyhelminth). Bioessays  28(5):546-559; 2006

Saló, E. Control genético del desarrollo del ojo. Investigación y Ciencia Noviembre 2004; ESP, Review

Mannini, L., Rossi, L.,  Deri, P., Gremigni, V., Salvetti, A.,  Saló, E. & Batistoni, R. Djeyes absent (Djeya) controls prototypic planarian eye regeneration by cooperating with the transcription factor Djsix-1. Developmental Biology 269; 346-359; 2004

Cook, C., Jiménez, E., Akam, M. & Saló, E. The Hox gene complement of Acoel flatworms, a basal bilaterian clade. Evol. & Dev. 6:3; 154-163; 2004

Gonzalez-Estevez, C., Momose, T., Gehring, W.J. & Saló, E. Planarian transgenic lines obtained by electroporation using transposon-derived vectors and eye-specific GFP marker. Proc. Natl. Acad. Sci. 100; no 24; 14046-14051; 2003

Marsal, M., Pineda, D.& Saló, E. Gtwint-5 a member of the wnt family expressed in the central nervous system of Platyhelminthes. Mech. Dev G E P 3; 489-495; 2003

Pasquinelli, A.E., McCoy, A., Jimenez, E., Saló, E., Ruvkum, G., Martindale, M.Q. & Baguñà, J. Expression of the 22 nucleotide let-7 heterocronic RNA throughout the Metazoa: A role in life history evolution?. Evol. & Dev. 5; 4; 372-378; 2003

Pineda, D., Saló, E. Planarian Gtsix3, a member of the Six/so gene family, is expressed in brain branches but not in eye cells Mech. Dev G E P. 2;169-173; 2002

Shagin, D.A., E.V. Barsova, E. Bogdanova, O.V. Britanova, N. Gurskaya, K.A. Lukyanov, M.V. Matz, N.I. Punkova, N.Y. Usman, E.P. Kopantzev, E. Saló, and S. Lukyanov. Identification and characterization of a new family of C-type lectin-like genes from planaria Girardia tigrina.  Glycobiology  12; 463-72; 2002

Saló , E., Pineda, D., Marsal, M., Gonzalez, J., Gremigni, V. & Batistoni, R. Eye genetic network in Platyhelminthes: Expression and functional analysis of some players during planarian regeneration Gene 287; 67-74; 2002; Ned; Review

Saló, E & Baguñà, J.  Regeneration in Planarians and other worms. New findings, new tools and new perspectives. J. Exp. Zool. 292: 528-539; 2002; USA ; Review

Pineda, D., Rossi, A., Batistoni, R., Salvetti, A., Marsal, M., Gremigni, V., Falleni, A., Gonzalez, J., Deri, P. & Saló , E. The genetic network of prototypic planarian eye regeneration is Pax-6 independent. Development 129: 1423-1434; 2002

Pineda, D., Gonzalez, J., Marsal, M. & Saló , E.  Functional analysis of the eye genetic network in planarian regeneration Int.J. Dev. Biol. 45 (Supplement 1): 123-124; 2001

Saló, E., Tauler, J., Jimenez, E., Bayascas, J.R., Gonzalez-Linares, J., Garcia-Fernàndez, J. & Baguñà, J. Hox and ParaHox genes in flatworms. Characterization and expression.. American Zoologist 41: 652-663; 2001

Pineda, D., Gonzalez, J., Marsal, M. & Saló , E. Evolutionary conservation of the initial eye genetic pathway in planarians. J. Bel. Zool. 131(Supplement 1): 77-82; 2001

Pineda, D., Gonzalez, J., Callaerts, P., Ikeo, K., Gehring, W.J. & Saló, E. Searching for the prototypic eye genetic network: sine oculis is essential for eye regeneration in planarians. Proc. Natl. Acad. Sci. 97: 9, 4525-4529; 2000

Callaerts, P., Munoz-Marmol, A.M., Glardon S., Castillo, E., Sun, H., Li, W-H ,  Gehring, W.J. & Saló, E. Isolation and expression of a Pax-6 gene in the regenerating and intact PlanarianDugesia(G)tigrina. Proc. Natl. Acad. Sci. 96: 558-563; 1999

Bayascas-Ramírez, J. R.,Castillo, E., Muñoz-Mármol, A. M. Baguñà, J. & Saló,E. Synchronous and early activation of planarian Hox genes and re-specification of body axes during regeneration. Hydrobiologia. 383: 125-130; 1998

Stornaiuolo A, Bayascas JR, Saló E,  Boncinelli E. A homeobox gene of the orthodenticlefamily is involved in antero-posterior patterning of regenerating planarians. Int. J. Dev. Biol. 42: 1153-1158; 1998.

Bayascas, J. R., Castillo, E., and Saló, E. Platyhelminthes have a Hox code differentially activated during regeneration, with genes closely related to those of spiralian protostomes. Dev. Genes. Evol. 208; 467-473; 1998

Muñoz-Màrmol, A. M., Casali, A., Miralles, A., Bueno, D., Bayascas, J. R., Romero, R., and Saló, E..Characterization of Platyhelminth POU domain genes: ubiquitous and specific anterior nerve cell expression of different epitopes of GtPOU-1.  Mech. Dev 76; 127-140; 1998

Muñoz-Mármol, A. M., Bayascas-Ramírez, J. R.,Castillo, E., Casali, A. & Saló,E.. Planarian homeobox gene Dtprd-1 is expressed in specific gland cells, and belongs to a new family within the paired-like class. Dev. Genes Evol. 207 (5), 296-305, 1997

Bueno, D., Castillo, E., Vispo, M., Cebria, F., Bayascas-Ramírez, J. R., Saló, E.& Romero, R. New protocol to visualize gene expression in intact and regenerating adult planarians by whole-mount in situ hybridization. (t01222). Tech. Tips on line, 12/11/1997

Tauler, J., Baguñà, J.  Saló & Garcia-Fernàndez, J. Distox genes: A milestone in the evolution of Hox clusters? Int.J. Dev. Biol. Supplement 1; pp 69S-70S; 1997

Bayascas-Ramírez, J. R.,Castillo, E., Muñoz-Mármol, A. M. & Saló,E. Planarian Hox genes: novel patterns of expression during regeneration. Development 124; pp. 141-148; 1997

Saló E, Muñoz-Marmol, A.M., Bayascas-Ramirez J.R., García-Fernández J., Casali, A., Corominas, M., &Baguñà J. The freshwater planarian Dugesia(G)tigrina.contains a great diversity of homeobox genes. Hydrobiologia, 305, 269-275;1995

Garcia-Fernàndez, J., Bayascas-Ramírez, J. R., Marfany, G., Muñoz-Mármol, A. M., Casali,  A., Baguñà, J.  & Saló, E. High copy number of highly conserved mariner-like transposons in planarian (Platyhelminthe): Evidence for a trans-phyla horizontal transfer. Mol. Biol. Evol. 12, 421-431; 1995

Baguñà, J., Saló, E., Romero, R., Garcia-Fernàndez, J., Bueno, D., Muñoz-Mármol, A. M., Bayascas-Ramírez, J. R. & Casali, A. Regeneration and pattern formation in planarians: Cells, molecules and genes. Zool. Sci. 11, No6, 781-795; 1994; JPN; Review.

Burgaya F., García-Fernández J., Riutort M., Baguñà J., & Saló E. Structure and expression of spk-1, a src-related gene product found in the simple triblastic Dugesia(G)tigrina.. Oncogene  9, 1267-1272; 1994.

Garcia-Fernàndez, J., Marfany, G., Baguñà, J. & Saló E. . Mariner, ¿de simple transposón a vector general de integración? Investigación y Ciencia, Diciembre (1993), 32-35

García-Fernández J., Marfany, G., Baguñà J., Saló E. Infiltration of mariner elements. Nature(Lond).364, 109-110 (1993) (Scientific Correspondence)

García-Fernández J., Baguñà J.,  Saló E.. Genomic organization and expression of the planarian homeobox genes Dth-1 and Dth-2. Development. 118; pp. 241-253; 1993

García-Fernández J., Baguñà J., Saló E.. Planarian Homeobox genes: Cloning, sequence analysis, and expression. Proc. Natl. Acad. Sci. 88; pp. 7338-7342; 1991

Saló E, Baguñà J. Regenation and pattern formation in planarians. III. Evidence that neoblasts are tolipotent stem-cells and the source of blastema cells . Development. 107; pp. 77; 86; 1989

Saló E, Baguñà J. Regeneration and pattern formation in planarians. II. Local origin and role of cell movements in blastema formation. Development  107; pp. 69; 76; 1989

Baguñà J., Saló E. Romero R.. Effects of activators and antagonists of the neuropeptides substance P and substance K on cell proliferation in planarians. Int. J. Dev. Biol. 33 pp. 261; 264; 1989

Saló E., Baguñà J. Changes in ornithine decarboxilase activity and polyamine content and effects of polymine inhibitors in the regenerating planarian Dugesia (G)tigrina. J. Exp. Zool. 250; pp. 150; 161; 1989

Baguñà J., Saló E., Collet J., Auladell M.C., Ribes M. Cellular, molecular and genetic approaches to regeneration and pattern formation in planarians. Fortschr. Zool.. 36; pp. 65; 78; 1988

Saló E, Baguñà J. Stimulation of cellular proliferacion and diferentiation in the intact regenerating planarian D. tigrina by the neuropeptide Substance P. J. of Experimental Zoology . 237; 1; 129; 136; 1986

Robertis E.M. Fritz A, Goetz J, Martin G, Mattaj I.W., Saló E, Smith G.D, Wright C, Zeller R.. The Xenopus homeoboxes. Cold Spring Harbor Symposia on Quantitative Biology. 50; 271; 276; 1985

Saló E, Baguñà J. Proximal and distal transformation during intercalary regeneration in the planarian D. tigrina. Evidence using a chromosomal marker. Roux´Archives of Developmental Biology. 194; pp. 364; 368; 1985

Saló E, Baguñà J. Cell movement intact and regenerating planarians. Quantitation using chromosomal, nuclear and cytoplasmatic markers. J. Embryol. exper. Morphol. 89; pp. 57; 70; 1985

Saló E, Baguñà J. Regeneration and pattern formation in planarians. I. The pattern of mitosis in anterior and posterior regeneration in D. tigrina. J. Embryol. exper. Morphol. 83; pp. 63; 80; 1984

Book chapters

Cebrià, F.; Adell, T.; Abril, J.F.; Saló, E. La regeneració i l’homeòstasi en les planàries, un model clàssic de biologia del desenvolupament. Book chapter in: Treballs de la Societat Catalana de Biología, “Organismes model en biología”, M. Corominas & M. Valls eds., Vol 62, pp: 93-106, 2011

Adell, T., Cebrià, F. Saló, E. Planarian totipotent stem cells.Stem Cells. In press (United States of America): Science Publishers, Inc., Enfield (NH), USA, Plymouth, UK, 2013

Francesc Cebrià, Teresa Adell, Emili Saló. Regenerative medicine: lessons from planarians. Book Chapter : Stem cells, regenerative medicine and cancer. Elsevier, 2010

Teresa Adell, Francesc Cebrià and Emili Saló. Gradients in planarian regeneration and homeostasis. Generation and Interpretation of Morphogenetic Gradients Editors: James Briscoe, Peter Lawrence, and Jean-Paul Vincent. Cold Spring Harbor Laboratory Press, 2010

Emili Saló and Renata Batistoni. Animal models in eye research ed. P.A. Tsonis Book Chapter: Planarian eye, a simple and plastic system with great regenerative capacity. Elsevier, 2008

Bueno, D. Romero, R. &Saló, E.RNAi techniques applied to freshwater planarians (Platyhelminthes) during regeneration. In J. Knight, M. Marí-Beffa (ed.), Key Techniques in Practical Developmental Biology. Cambridge University Press, Cambridge. In press; 2005

Saló, E., Watson, N. & Schockaert, E. Proceedings of the 9th International Symposium on The Biology of the Turbellaria. J. Bel. Zool. 131(Supplement 1); 2001;  236 pp.; Bel; E

Baguñà J., Romero R., Saló E. et al.. Growth /degrowth amd regeneration as development phenomena in adult freshwater planarians. “Experimental Embryology in aquatic Plant and Animal Organisms” NATO-ASI Series H.J. Marthy, Plenum Press. pp. 129-162; 1990;  New York; USA; Review